# METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV

> **NIH NIH R33** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $719,829

## Abstract

Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the
etiological agent of TB. Co-infection with HIV and the spread of multidrug-resistant (MDR) and extensively drug-
resistant (XDR) Mtb strains constitutes a major impediment to worldwide public health control measures. T cell
exhaustion, defined as the deterioration of T cell function, is a hallmark of many chronic infections due to
prolonged antigen exposure and inflammatory signals present at the site of infection. However, very little is
known regarding the link between these functionally exhausted cells and their metabolic insufficiencies,
particularly in the context of the human TB/HIV lung. Given that immune activation is critically energy-dependent,
and that pathogens cause imbalances in metabolism, there is a gap in our knowledge on how Mtb/HIV
reprograms immunometabolic pathways, and whether this can be reversed by host-directed therapy (HDT) to
rejuvenate T cell metabolism. Our long-term goal is to understand how Mtb/HIV perturbs host metabolism leading
to disease, reactivation, or death of the host, and how this knowledge can be leveraged for therapeutic purposes.
Our central hypothesis is that Mtb/HIV dysregulates T cell energy metabolism in the human lung, leading to the
suppression of effective immune control of localized infection, which could be restored by HDT. This hypothesis
has been formulated based on an unusual global collaborative effort between basic science investigators,
cardiothoracic surgeons, and pathologists in South Africa, and epigenetic, proteomic and metabolomic experts
in the USA and Europe. Our hypothesis is built upon substantial Preliminary Data which demonstrate the
feasibility of routine analyses of freshly resected human TB lung tissue, and show that Mtb controls distinct
bioenergetic pathways and immune checkpoints. The rationale is several fold: Firstly, phenotypic
characterization of functionally exhausted T cell populations has been largely restricted to animal models, and
to date, there have been no studies examining these populations from freshly resected human TB/HIV lung
tissue, representing a significant translational gap in our knowledge. Secondly, examining the metabolic
requirements of functionally exhausted T cell populations in the human TB/HIV lung will enable us to identify key
metabolic checkpoints that may represent novel pharmacological targets for HDT. With greater knowledge of the
metabolic checkpoints involved in T cell exhaustion, HDT may be a possible intervention strategy to revitalize
these cells and reinvigorate anti-TB immunity. Thirdly, identifying nutritional requirements and metabolic
pathways that promote productive T cell responses and hinder the transition towards exhausted T cell programs
could provide exciting new benchmarks for TB/HIV vaccine design. The research is innovative, because it
represents a new and substantive departure from the status quo by applying ...

## Key facts

- **NIH application ID:** 10092517
- **Project number:** 4R33AI138280-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** ADRIE JC STEYN
- **Activity code:** R33 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,829
- **Award type:** 4N
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10092517

## Citation

> US National Institutes of Health, RePORTER application 10092517, METABOLIC REPROGRAMMING OF T CELL ENERGY METABOLISM IN TUBERCULOSIS AND HIV (4R33AI138280-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10092517. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*